ASO-mediated depletion of toxic mutant proteins is likely to be most critical in ALS, and should be joined with a gamut of neuroprotective accessory therapies such as neurotrophic factors (Henriques et al., 2010), SMN upregulation (e.g., via nusinersen or AVXS-101) (Kariya et al., 2012; Turner et al., 2014), and preservation of NMJ innervation (Miyoshi et al., 2017), in order to determine the most efficacious drug combinations. This evidence concerns the gene SMN2 and amyotrophic lateral sclerosis.